RS51235B - N- (AMINOHETEROARYL) -1H-INDOL-2-CARBOXAMIDE DERIVATIVES, THEIR PRODUCTION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

A compound of formula (I) wherein X1 is a hydrogen atom or a halogen atom or C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, cyano, C ( O) NR1R2, nitro, C1-C6-thioalkyl, -S (O) -C1-C6-alkyl, -S (O) 2-C1-C6-alkyl, SO2NR1R2, aryl-C1-C6-alkylene, aryl or heteroaryl a group wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl , C1-C6-alkoxyl, C1-C6-fluoroalkoxyl, nitro or cyano groups; X2 is a hydrogen atom or a halogen atom or C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxy, C3-C7-cycloalkoxy, C3-C7-cycloalkyl-C1-C6-alkylene-O-, C1-C6-fluoroalkoxy, cyano, C (O) NR1R2, C1-C6-thioalkyl, -S (O) -C1-C6-alkyl, -S ( O) 2-C1-C6-alkyl, SO2NR1R2, aryl-C1-C6-alkylene, aryl or heteroaryl group, wherein aryl and heteroaryl are optionally substituted by one or more halogen-selected substituents, and C1-C6-alkyl. C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxyl, C1-C6-fluoroalkoxy, nitro or cyano groups; X3 and X4 are, independently of one another, a hydrogen or halogen atom or C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxyl , C3-C7-cycloalkoxy, C3-C7-cycloalkyl-C1-C6-alkylene-O-, C1-C6 fluoroalkoxy, cyano, C (O) NR1R2, nitro, NR1R2, C1-C6-thioalkyl, -S (O) -C1-C6 alkyl, -S (O) 2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5, aryl-C1-C6-alkylene, aryl or heteroaryl group, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxyl, C1-C6-fluoroalkoxy, nitro or cyano groups; Z1, Z2, Z3 and Z4 are, independently of one another, a nitrogen atom or a C (R6) group, with at least one corresponding to the nitrogen atom and at least one corresponding to the C (R6) group; And wherein the nitrogen atom or one of the nitrogen atoms present in the ring, defined as nitrogen in position 1, is optionally substituted with R7 when the carbon atom in position 2 or position 4 with respect to the reference nitrogen is substituted with an oxo or thio group; n is 0, 1, 2 or 3; Y is aryl or heteroaryl optionally substituted by one or more groups selected from halogen atoms or C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3- alkylene, C1-C6-fluoroalkyl, hydroxyl, C1-C6-alkoxyl, C3-C7-cycloalkoxy, C3-C7-cycloalkyl-C1-C6-alkylene-O-, C1-C6-fluoroalkoxy, cyano, C (O) NR1R2 , nitro, NR1R2, C1-C6-thioalkyl, thiol, -S (O) -C1-C6-alkyl, -S (O) 2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5, aryl-C1-C6- alkylene or aryl group, wherein aryl and aryl-C1-C6-alkylene are optionally substituted with one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1- C3-alkylene, C1-

Description

[0001] The invention relates to compounds, derivatives of N-(aminoheteroaryl)-1H-indole-2-carboxamide that show in vitro and in vivo antagonistic activity against TRPV1 (or VR1) type receptors.

[0002] WO 2006/072736 describes derivatives of N-(heteroaryl)-1H-indole-2-carboxamide which are used as ligands of the vanilloid receptor TRPV1.

[0003] The first purpose of the invention relates to the compounds corresponding below

to the general formula (I) shown.

Another purpose of the invention relates to processes for obtaining compounds of formula (I). The next purpose of the invention relates to the use of compounds of formula (I), especially in drugs or pharmaceutical compositions.

[0004] The compounds of the invention correspond to the general formula (I):

in which

Xi represents a hydrogen atom or a halogen atom or Ci-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, CrC6-fluoroalkyl, cyano, C(0)NRiR2, nitro, d-Ce-thioalkyl, -S(O)- CrC6 -alkyl, -S(0)2- CrC6-alkyl, S02N R1R2>aryl- d-C6 - an alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-d-d-alkylene, d-C6-fluoroalkyl, C1-C6-methoxy, C1-C6-fluoroalkyl, nitro or cyano groups;

X2 represents a hydrogen atom or a halogen atom or d-Ce-alkyl, C3-C7-cycloalkyl,

C3-C7-Cycloalkyl-Ci-C3-alkylene, CrC6-Fluoroalkyl, d-C6-Alkoxyl, C3-C7-Cycloalkoxyl, C3-C7-Cycloalkyl-Ci-C6-Alkylene-0-, Ci-C6-Fluoroalkylene, Cyano, C(0)NRiR2, d-Ce-thioalkyl, -S(0)-d-C6-Alkyl. -S(O)2-d-C6-alkyl, SO2NRiR2, aryl-d-C6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and d-C6-alkyl, C3-d-cycloalkyl, C3-C7-cycloalkyl-d-C3-alkylene, d-C6-fluoroalkyl, d-C6-Alkoxyl, d-C6-Fluoro-Alkoxyl, nitro or cyano groups;

X3 and X4 represent, independently of each other, a hydrogen or halogen atom or d-Ce-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-d-C3-alkylene, Ci-C6-fluoroalkyl, d-Ce-alkoxy, C3-Crcycloalkyl, C3-d-cycloalkyl-d-C6-alkylene-0-, d-C6-fluoroalkylene, cyano, C(0)NRiR2, nitro, NR1R2, d-C6-thioalkyl, -S(0)-CrC6-alkyl, -S(0)2-Ci-C6-alkyl, SO2NRiR2) NR3COR4, NR3S02R5, aryl-d-C6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and d-C6-alkyl, C3-C7-cycloalkyl, d-d-cycloalkyl-d-C3-alkylene, d-C6-fluoroalkyl, d-C6-alkyl, C1-C6-fluoroalkyl, nitro or cyano groups;

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a nitrogen atom or a C(Re) group, wherein at least one corresponds to a nitrogen atom and at least one corresponds to a C(R 6 ) group; And wherein the nitrogen atom or one of the nitrogen atoms present in the ring, defined as nitrogen in position 1, is optionally substituted with R7 when the carbon atom is in position 2 or position 4 relative to the reference

nitrogen substituted with an oxo or thio group;

n is equal to 0, 1, 2 or 3;

Y represents aryl or heteroaryl optionally substituted with one or more groups selected from a halogen atom or d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-d-C3-alkylene, d-C6-fluoroalkyl, hydroxyl, d-C6-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkyl-d-C6-alkylene-0-, d-C6-fluoroalkyl, cyano, C(0)NR1R2lnitro, NRiR2, d-C6-thioalkyl, thiol, -S(0)-d-C6-alkyl, -S(0)2-d-Ce-alkyl, SOzNF^Rz, NR3COR4, NR3SO2R5, aryl-d-C6-alkylene or aryl group, wherein aryl and aryl-C-1C6-alkylene optionally substituted with one or more substituents selected from halogen, and d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkyl, C1-C6-fluoroalkyl, nitro or cyano groups;

Z represents a cyclic amine attached via a nitrogen atom, formula

in which

A is a C1-C7-alkylene group optionally substituted with one or two R8 groups;

B is a C1-C7-alkylene group optionally substituted with one or two R9 groups;

L is a bond, or a sulfur, acid or nitrogen atom, wherein the nitrogen atom is optionally substituted with the group R10 or Rn,

the carbon atoms of the cyclic amine Z are optionally substituted with one or

multiple groups R12 which can be identical or different from each other;

R 1 and R 2 are, independently of each other, a hydrogen atom or a C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-d-C 6 -alkylene, aryl or heteroaryl group; or R1 and R2 are, together with the nitrogen atom bearing them, an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, wherein this group is optionally substituted with a CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, aryl-d-C6-alkylene, aryl or heteroaryl group;

R 3 and R 4 are, independently of each other, a hydrogen atom or a C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene, aryl or heteroaryl group;

R5 is a d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene)aryl-d-C6-alkylene, aryl or heteroaryl group;

R6 represents a hydrogen or halogen atom or C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, d-C6-fluoroalkyl, d-C6-alkyl, C3-C7-

cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene-0-, d-C6-fluoroalkyl, d-C6-thioalkyl, -S(0)-CrC6-alkyl, -S(0)2-d-C6-alkyl, aryl, aryl-d-C6-alkylene, heteroaryl, hydroxyl, thiol, oxo or thio group;

R7 represents a hydrogen atom or a d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, d-C6-fluoroalkyl, CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkylene-0-, d-C6-fluoroalkylene, aryl, aryl-CrC6-alkylene or heteroaryl group;

R8. R9 and R10 are defined so that::

two R8 groups can together form a bond or a d-C6-alkylene group;

two R9 groups can together form a bond or a d-C6-alkylene group;

Rb and Rg can together form a bond or a d-C6-alkylene group;

R and R 10 may together form a bond or a d-C 6 -alkylene group;

R9 and R10 may together form a bond or a d-C6-alkylene group;

R11 represents a hydrogen atom or a d-C6-alkyl, C3-d-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, d-C6-fluoroalkyl, d-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-d-Ce-alkylene-O-, d-C6-fluoroalkyl, hydroxyl, COOR5, C(0)NRiR2, aryl-Ci-C6-alkylene, aryl or heteroaryl group, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-d-C3-alkylene, d-C6-fluoroalkyl, d-C6-alkyl, C3-C7-cycloalkyl, Ci-C6-fluoroalkyl,

nitro or cyano groups;

Ri2 is a fluorine atom, a d-C6-alkyl group optionally substituted with a group R-|3,

C3-C7-cycloalkyl, d-d-cycloalkyl-d-C3-alkylene, d-C6-fluoroalkyl or CrC6-cycloalk-1,1-diyl group, C3-C7-heterocycloalk-1,1-diyl group optionally substituted on the nitrogen atom with the group Rn, or d-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-C1-C6-alkylene-0-, C1-C6-fluoroalkyl, C(0)NRiR2, NRiR2, NR3COR4, OdOJNR^, NR3COOR5, NR3CONR-iR2i hydroxyl, thiol, oxo, thio, aryl-d-C6-alkylene j|j aryl group, wherein the aryl is optionally substituted with one or more substituents selected from from halogen, and d-Ce-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-C1-C3-alkylene, d-C6-fluoroalkyl, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-fluoroalkyl, nitro or cyano groups;

R-13 is C1-C6-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene-O-, C(O)NR1R2)NR1R5, NR3COR4)OC(O)NR1R2, NR3COOR5 or hydroxyl;

[0005] In the compounds of the general formula (I), the nitrogen atom(s) may be in an oxidized form (N-oxide).

In compounds of general formula (I), the sulfur atom(s) may be in the oxidized form (S(O) or S(O)2).

[0006] As non-limiting examples of amine Z, aziridine, azetidine, pyrrolidines, piperidine, azepine, morpholine, thiomorpholine, piperazine, homopiperazine, azabicyclo[3.3.0]octanes, octahydrofuropyrroles, octahydropyrrolopyrroles, octahydroindole, octahydroisoindole, octahydropyrrolopyridines, decahydroquinoline, decahydroisoquinoline, decahydronaphthyridines, octahydropyridopyrazines, azabicyl[3.1.0]hexanes, azabicyl[3.2.0]heptanes, azabicyl[3.1.1]heptanes, diazabicyl[2.2.1]heptanes, azabicyl[3.2.1]octanes, diazabicyl[3.2.1]octanes and azabicyl[3.3.1]nonanes.

[0007] Among the compounds of the general formula (I) that are the subject of the invention, the first subgroup of compounds consists of compounds for which X-i, X2, X3 and X4 are selected, independently of each other, from hydrogen atoms or halogen atoms or Ci-C6-alkyl, Ci-C6-fluoroalkyl, C-p Ce-thioalkyl or -S(0)2-Ci-C6-alkyl groups.

[0008] Among the compounds of the general formula (I) which are the subject of the invention, the second subgroup of compounds consists of compounds for which X-i, X2, X3 and X4 are selected, independently of each other, from hydrogen atoms or halogen atoms or Ci-C6-alkyl or Cr-C6-fluoroalkyl groups.

[0009] Among the compounds of the general formula (I) that are the subject of the invention, the third subgroup of compounds consists of compounds for which X-i, X2, X3 and X4 are selected, independently of each other, from hydrogen atoms or fluorine or chlorine atoms or methyl, ethyl,

isopropyl, tert-butyl, trifluoromethyl, thiomethyl or -S(0)2CH3 groups.

[0010] Among the compounds of the general formula (I) that are the subject of the invention, the fourth subgroup of compounds consists of compounds for which

Xi represents a hydrogen atom or a halogen atom or a C1C6-alkyl group;

X2 represents a hydrogen atom or a halogen atom or a Ci-C6-alkyl group, a Ci-C6-fluoroalkyl or - S(O)2-CrC6-alkyl group;

X 3 and X 4 are, independently of each other, a hydrogen or halogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, NR-]R 2 or C 1 -C 6 -thioalkyl group;

R 1 R 2 are, independently of each other, a C 1 -C 6 -alkyl group.

[0011] Among the compounds of formula (I) that are the subject of the invention, the fifth subgroup of compounds consists of compounds for which

Xi is a hydrogen, fluorine or chlorine atom or a methyl group;

X2 is a hydrogen, fluorine or chlorine atom or a methyl, isopropyl, tert-butyl, trifluoromethyl or - S(0)2CH3 group;

X 3 and X 4 are, independently of each other, a hydrogen, fluorine or chlorine atom or a methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, -O-isopropyl, NR^ or thiomethyl group;

R 1 R 2 are, independently of each other, a methyl group.

[0012] Among the compounds of the general formula (I) that are the subject of the invention, the sixth subgroup of compounds consists of compounds for which

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a nitrogen atom or a C(Re) group, with at least two of them corresponding to a C(R 6 ) group; and wherein the nitrogen atom or one of the nitrogen atoms present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or position 4 relative to the reference nitrogen is substituted with an oxo or thio group;

R 6 and R 7 are defined as in general formula (I).

[0013] Among the compounds of the general formula (I) that are the subject of the invention, the seventh subgroup of compounds consists of compounds for which Z 1 and Z 3 represent a C(Re) group and Z 2 and Z 4 represent a nitrogen atom; R 6 is defined as in general formula (I).

[0014] Among the compounds of the general formula (I) that are the subject of the invention, the eighth subgroup of compounds consists of compounds for which Z, and Z3 represent a C(R6) group and Z2 and Z4 represent a nitrogen atom; where R$ corresponds to a hydrogen atom.

[0015] Among the compounds of the general formula (I) that are the subject of the invention, the ninth subgroup of compounds consists of compounds for which

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a nitrogen atom or a C(R 6 ) group, where one of them corresponds to a nitrogen atom and the other corresponds to a C(Re) group; And wherein the nitrogen atom present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or position 4 relative to that reference nitrogen is substituted with an oxo or thio group;

R 6 and R 7 are defined as in general formula (I).

[0016] Among the compounds of the general formula (I) which are the subject of the invention, the tenth subgroup of compounds consists of compounds for which Z4 represents a nitrogen atom and Z1, Z2 and Z3 represent, independently of each other, a C(R6) group, wherein the nitrogen atom present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or position 4 in relation to that reference nitrogen is substituted with oxo or thio group;

R 6 and R 7 are defined as in general formula (I).

[0017] Among the compounds of the general formula (I) that are the subject of the invention, the eleventh subgroup of compounds consists of compounds for which Z4 represents a nitrogen atom and Z1, Z2 and Z3 represent, independently of each other, a C(R6) group; R 6 is a hydrogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl or C 1 -C 6 -alkoxy group.

[0018] Among the compounds of the general formula (I) that are the subject of the invention, the twelfth subgroup of compounds consists of compounds for which Z4 represents a nitrogen atom and Z-i, Z2 and Z3 represent, independently of each other, a C(R6) group; R6 is a hydrogen atom or a methyl, trifluoromethyl or methoxy group.

[0019] Among the compounds of the general formula (I) that are the subject of the invention, the thirteenth subgroup of compounds consists of compounds for which n is equal to 1.

[0020] Among the compounds of the general formula (I) that are the subject of the invention, the fourteenth subgroup of compounds consists of compounds for which Y is aryl or heteroaryl optionally substituted with one or more groups selected from a halogen atom or a C1C6-alkyl or NR1R2 group;

Ri and R2 are, together with the nitrogen atom bearing them, an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, wherein this group is optionally substituted with a Ci-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-CrC3-alkylene, aryl-Ci-C6-alkylene, aryl or heteroaryl group.

[0021] Among the compounds of the general formula (I) that are the subject of the invention, the fifteenth subgroup of compounds consists of compounds for which Y is phenyl or pyridinyl, wherein phenyl is optionally substituted with a group selected from a fluorine atom or a methyl or NR1R2 group;

Ri and R2, together with the nitrogen atom bearing them, form the pyrrolidinyl group.

[0021] Among the compounds of the general formula (I) that are the subject of the invention, the sixteenth subgroup of compounds consists of compounds for which

Z is a cyclic amine attached via a nitrogen atom, formula:

in which

A represents a C 1 -C 4 -alkylene group optionally substituted with one or two R s groups; B i represents a C 1 -C 4 -alkylene group optionally substituted with one or two R 9 groups;

L is a bond or an oxygen atom;

where it is possible for the atpm nitrogen of the cyclic amine Z to be in the form of N-oxide;

wherein the carbon atoms of the cyclic amine Z are optionally substituted with an R12 group; R8 and Rg are defined so that:

two R8 groups can build a connection together; or

two Rg groups can build a bond together; or

R8 and R9 can build a connection together;

R 12 represents NR 1 R 2 , NR 3 COOR 5 or a hydroxy group;

R 1 and R 2 represent, independently of each other, a hydrogen atom;

R3 is a hydrogen atom;

R5 is a C1-C6-alkyl group.

[0023] Among the compounds of the general formula (I) that are the subject of the invention, the seventeenth subgroup of compounds consists of compounds for which

Is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyl[3.1.0]hexane and azabicyl[3.2.0]heptane;

whereby it is possible for the nitrogen atom of the cyclic amine to be in the form of N-oxide;

wherein it is possible for the carbon atoms of the cyclic amine Z to be optionally substituted with the R12 group;

R 12 represents NR 1 R 2 , NR 3 COOR 5 or a hydroxyl group;

R 1 R 2 , independently of each other, represent a hydrogen atom;

R3 represents a hydrogen atom;

R5 is a C1-C6-alkyl group.

[0024] Among the compounds of the general formula (I) that are the subject of the invention, the eighteenth subgroup of compounds consists of compounds for which

Is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyl[3.1.0]hexane and azabicyl[3.2.0]heptane;

whereby it is possible for the nitrogen atom of the cyclic amine to be in the form of N-oxide;

wherein it is possible for the carbon atoms of the cyclic amine Z to be optionally substituted with an R-12 group

R 12 represents NR 1 R 2 , NR 3 COORsilyl hydroxyl group;

R 1 R 2 , independently of each other, represent a hydrogen atom;

R3 represents a hydrogen atom;

R is a tert-butyl group.

[0025] Among the compounds of the general formula (I) that are the subject of the invention, the nineteenth subgroup of compounds consists of compounds for which

Z is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyl[3.1.0]hexane and azabicyl[3.2.0]heptane;

wherein the carbon atoms of azetidine are optionally substituted with a hydroxyl group;

wherein the pyrrolidine carbon atoms are optionally substituted with NR 1 R 2 , NR 3 COOR 5 or

hydroxyl group; whereby it is possible for the nitrogen atom of pyrrolidine to be in the form of N-oxide;

R 1 R 2 , independently of each other, represent a hydrogen atom;

R3 represents a hydrogen atom;

R is a tert-butyl group.

[0026] Among the compounds of the general formula (I) that are the subject of the invention, the twentieth subgroup of compounds consists of compounds for which

Z is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyl[3.1.0]hexane and azabicyl[3.2.0]heptane;

wherein the carbon atoms of azetidine are optionally substituted with a hydroxyl group;

wherein the pyrrolidine carbon atoms are optionally substituted with NR 3 , NR 3 COOR 5 or a hydroxyl group; whereby it is possible for the nitrogen atom of pyrrolidine to be in the form of N-oxide;

R 1 R 2 , independently of each other, represent a hydrogen atom;

R3 represents a hydrogen atom;

R is a tert-butyl group.

[0027] Among the compounds of the general formula (I) that are the subject of the invention, the twenty-first subgroup of compounds consists of compounds for which

Z is a cyclic amine attached via a nitrogen atom, formula:

in which

A represents a C1-C7-alkylene group optionally substituted with one or two R8 groups; B represents a C 1 -C 7 -alkylene group optionally substituted with one or two R 8 groups; L is a bond, a sulfur atom, oxygen or nitrogen, wherein the nitrogen atom is optionally substituted with the group R10 or Rn,

the carbon atoms of the cyclic amine Z may optionally be substituted with one or more R 12 groups, which may be identical or different from each other, wherein R 12 is a Ci-C 6 -alkyl group optionally substituted with the group R 13 , NR-1R 2 or NR 3 COOR 5 ;

P m i R 2 , independently of each other, represent a hydrogen atom or a C 1 -C 6 -alkyl group; R3 represents a hydrogen atom or a C1-C6-alkyl group;

R5 is a C1-C6-alkyl group.

R8, R9 and R10 are defined so that:

two R8 groups can together form a bond or a d-C6-alkylene group; or two R9 groups can together form a bond or a d-C6-alkylene group;; or R 8 and R 9 may together form a bond or a C-i-C 6 -alkylene group; or

R 8 and R 10 may together form a bond or a C 1 -C 6 -alkylene group; or

R 8 and R 10 can together form a bond or a C 1 -C 6 -alkylene group;

R 11 is defined as in general formula (I).

[0028] Among the compounds of the general formula (I) that are the subject of the invention, the twenty-second subgroup of compounds consists of compounds for which

It is a cyclic amine attached via a nitrogen atom, formula:

in which

A represents a C1-C7-alkylene group;

B represents a C1C7-alkylene group;

L is a bond, a sulfur atom, oxygen or nitrogen, wherein the nitrogen atom is optionally substituted with the group Rn,

the carbon atoms of the cyclic amine Z may optionally be substituted with one or more R 12 groups, which may be identical or different from each other,

R 11 and R 12 are as defined in general formula (I).

[0029] Among the compounds of the general formula (I) that are the subject of the invention, the twenty-third subgroup of compounds consists of compounds for which

Z represents an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, wherein this group is optionally substituted with one or more R12 groups, which may be identical or different from each other, wherein R12 is as defined in general formula (I).

[0030] Among the compounds of the general formula (I) that are the subject of the invention, the twenty-fourth subgroup of compounds consists of compounds for which

Z represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, wherein this group is optionally substituted with one or more R12 groups, which may be identical or different from each other,

R 12 is a C 1 -C 6 -alkyl group optionally substituted with the group R 13 , NR 1 R 2 or NR 3 COOR 5 ; R 1 and R 2 are, independently of each other, a hydrogen atom or a C 1 -C 6 -alkyl group;

R 3 is a hydrogen atom or a C 6 -alkyl group;

R5 is a C1-C6-alkyl group.

[0031] Among the compounds of formula (I) that are the subject of the invention, the twenty-fifth subgroup of compounds consists of compounds for which

Xi, X2, X3, X4, Z-i, Z2, Z3, Z4, n, Y and Z are as defined above in the subgroups.

[0032] Among the compounds of the general formula (I) that are the subject of the invention, the twenty-sixth subgroup of compounds consists of compounds for which

X 1 , X 2 , X 3 and X 4 are independently selected from a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl or C 1 -C 6 -fluoroalkyl group; and/or

Z1, Z2, Z3 and Z4 represent, independently of each other, a nitrogen atom or a C(R6) group, where one of them corresponds to a nitrogen atom and the other corresponds to a C(Re) group; And wherein the nitrogen atom present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or position 4 relative to that reference nitrogen is substituted with an oxo or thio group;

R 6 and R 7 are defined as in general formula (I); and/or

n is equal to 1; and/or

It is a cyclic amine attached via a nitrogen atom, formula:

in which

A represents a C1-C7-alkylene group;

B represents a (VC2-alkylene group;

L is a bond or an atom of sulfur, oxygen or nitrogen, wherein the nitrogen atom is optionally substituted with the group Rn,

the carbon atoms of the cyclic amine Z are optionally substituted with one or more R 12 groups, which may be identical or different from each other;

R 11 and R 12 are as defined in general formula (I).

[0033] Among the compounds of the general formula (I) that are the subject of the invention, the following compounds can be mentioned: 1. N-{6-[((R)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]pyridin-3-yl}-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 2. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 3. N-{6-[(R)-3-aminopyrrolidin-1-yl]pyridin-3-yl}-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 4. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 5. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 6. N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 7. N-[6-(3-hydroxypyrrolidin-1) -ii)pyridin-3-ii]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 8. N-[5-methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 9. N-[6-(pyrrolidin-1-yl)pyridin-3-yl] 1-[(pyridin-4-yl)methyl]-6-trifluoromethyl-1H-indole-2-carboxamide 10. N-[6-(pyrrolidin-1-yl)-4-methylpyridin-3-yl]-5-fluoro-1 -[(pyridin-4-yl)methyl]-1 H-indole-2-carboxamide 11. N-[5-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide 12. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-[3-(pyrrolidin-1-yl)benzyl]-1H-indole-2-carboxamide 13. N-[6-(piperidin-1-yl)pyridin-3-yl]-5-fluoro- 1-(3-fluorobenzyl)-1H-indole-2-carboxamide 14. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]- 1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1 H-indole-2-carboxamide 15. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl] 1-[(6-methylpyridin-2-yl)methyl]-1 H-indole-2-carboxamide 16. N-[4-methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro- 1-(3-fluorobenzyl)-1 H-indole-2-carboxamide 17. N-[6-(morpholin-4-yl)pyridin-3-yl]-5-fluoro-1 -(3-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (1:1) 18. N-[4-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide 19. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(2-methylpyridin-4-yl)methyl]-1H-indole-2-carboxamide 20. N-[6-(1-oxypyrrolidy-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 21. N-[2-(pyrrolidin-1-yl)pyrimidin-5-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 22. N-[6-(3-azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 23. N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-fluoro-1H-indole-2-carboxamide 24. N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 25. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 26. N-[6-(azetidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-fluoro-1 H-indole-2-carboxamide 27. N-[2-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-carboxamide 28. N-[6-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-carboxamide 29. N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]- 1-(3-fluorobenzyl)-5-trifluoromethyl-1 H-indole carboxamide 30. N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]- 1-(3-fluorobenzyl)-6-trifluoromethyl-1H-indole-2-carboxamide

31. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(benzyl)-1H-indole-2-carboxamide

32. N-[6-(azetidin-1-yl)pyridin-3-yl]-4,6-dimethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 33. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-tert-butyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 34. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-isopropyloxy-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 35. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-methylsulfonyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 36. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-dimethylamino -1-(3-fluorobenzyl)-1H-indole-2-carboxamide 37. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-methylthio- 1-(3-fluorobenzyl)-1H-indole-2-carboxamide 38. N-[6-(azetidin-1-yl)pyridin-3-yl]-4-fluoro- 1-(3-fluorobenzyl)-1H-indole-2-carboxamide 39. N-[6-(azetidin-1-yl)pyridin-3-yl]-7-fluoro -1-(3-fluorobenzyl)-1 H-indole-2-carboxamide 40. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide H-indole-2-carboxamide 41. N-[6-(azetidine-1 -yl)pyridin-3-yl]-4-chloro- 1-(3-fluorobenzyl)-1 H -indole-2-carboxamide 42. N-[6-(azetidin-1 -yl)pyridin-3-yl]-6-chloro-1 -(3-fluorobenzyl)-1 H -indole-2-carboxamide 43. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-chloro- 1-(3-fluorobenzyl)-1H-indole-2-carboxamide

44. N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

45. N-[6-(azetidin-1-yl)pyridin-3-yl]-4-methyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 46. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-methyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 47. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-methyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 48. N-[6-(azetidin-1-yl)pyridin-3-yl]-5-isopropyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 49. -yl)pyridin-3-yl]-5-tert-butyl-1-(3-fluorobenzyl)-1 H-indole-2-carboxamide

50. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-ethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

51. N-[6-{azetidin-1-yl)pyridin-3-yl]-6-isopropyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 52. N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 53. N-[6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

[0034] In the context of the present invention, the term: - Ct.Cz where 11 z can have values from 1 to 7 means a chain based on carbon atoms that can contain from 1 to 7 carbon atoms, for example, "C1-C3" means a chain of carbon atoms that contains from 1 to 3 carbon atoms.; - "alkyl" means: a linear or branched, saturated aliphatic group. By way of example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc., groups may be mentioned; - "alkylene" means a linear or branched, saturated divalent alkyl group, for example, a C1-C3-alkylene group is a linear or branched, divalent chain of carbon atoms containing from 1 to 3 carbon atoms, for example, methylene, ethylene, 1-methylethylene or propylene; - "acycloalkyl" means: a cyclic group based on carbon. By way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., groups may be mentioned; - "heterocycloalkyl" means a cyclic group with 3 to 7 ring members containing 1 or 2 heteroatoms selected from O, S or N;

- "cycloalkyl-1,1-idinyl" or "heterocycloalkyl-1,1-idinyl" denotes a group of the type

where D is a cycloalkyl or heterocycloalkyl group; - "fluoroalkyl" means an alkyl group in which one or more hydrogen atoms are substituted by a fluorine atom;

- "Alkoxy" means an -O-alkyl radical where the alkyl group is as defined above.

- "cycloalkyl" means: -O-cycloalkyl radical where the cycloalkyl group is as defined above; - "fluoroalkyl" means an oxy group in which one or more hydrogen atoms are substituted by a fluorine atom; - "thioalkyl" means an -S-alkyl radical where the alkyl group is as defined above; - "aryl" means: a cyclic aromatic group containing between 6 and 10 carbon atoms. As examples of aryl groups, phenyl or naphthyl groups may be mentioned; - "heteroaryl" means: an aromatic cyclic group with from 5 to 10 ring members, containing from 1 to 4 heteroatoms selected from O, S or N. As an example, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinoxalinyl groups; - "halogen atom" means: fluorine, chlorine, bromine or iodine; - "oxo" means "-O";

- "tio" means "-S".

[0035] The compounds of the general formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

[0036] The compounds of the general formula (I) can exist in the form of bases or addition salts of acids. Such addition salts form part of the invention.

These salts may conveniently be prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, in the purification or isolation of compounds of formula (I) also form part of the invention.

The compounds of the general formula (I) can be in the form of hydrates or solvates, ie, in the form of association or combination with one or more molecules of water or solvent. Such hydrates and solvates also form part of the invention.

[0037] In the text that follows, the term "leaving group" means a group that can be easily removed from a molecule by cleavage of a heterolytic bond, with the departure of a pair of electrons. This group can therefore, for example, be easily replaced by another group during a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and references for their preparation are given in "Advances in Organic Chemistry", J. March, 5m Edition, Wiley Interscience, 2001.

[0038] In accordance with the invention, compounds of general formula (I) can be obtained according to the process illustrated in Scheme 1 below.

[0039] According to scheme 1, compounds of the general formula (IV) can be obtained by reacting the compounds of the general formula (II) in which Xi, X2, X3 and X4 are as defined in the general formula (I) and B is a C-i-C6-alkyl group, with a compound of the general formula (III), in which Y in are as defined in the general formula (I) and GP is a leaving group, wherein GP is a hydroxyl group.

[0040] Compounds of general formula (II) are commercially available or can be obtained according to many processes described in the literature (D. Knittel Synthesis 1985, 2, 186; T. M. Williams J. Med. Chem. 1993, 36 (9), 1291; JP2001151771A2, for example).

[0041] When the compound of the general formula (III) is defined so that n is equal to 1, 2 or 3 and GP is a leaving group such as a chlorine, bromine or iodine atom, the reaction must be carried out in the presence of a base such as sodium hydride or potassium carbonate, in a polar solvent such as dimethylformamide, dimethyl sulfoxide or acetone (n=1: Kolasa T., Bioorg. Med. Chem. 1997, 5 (3) 507, n=2: Abramovitch R., Synth. Commun., 1995, 25 (1), 1).

When the compound of general formula (III) is defined so that n is equal to 1, 2 or 3 and GP is a hydroxyl group, compounds of general formula (IV) can be obtained by reacting a compound of general formula (II) with a compound of general formula (III) in the presence of a phosphine such as, for example, triphenylphosphine, and a reactant such as, for example, diethyl azodicarboxylate in a solvent solution, such as dichloromethane or tetrahydrofuran (O. Mitsonobu, Synthesis, 1981, 1 - 28).

[0043] When the compound of the general formula (III) is defined so that n is equal to 0, GP is a leaving group such as chlorine, bromine or iodine and the reaction can be carried out at a temperature between 80 °C and 250 °C, in the presence of a copper-based catalyst, which is copper bromide or copper oxide, and a base such as potassium carbonate (Murakami Y., Chem. Pharm. Buli., 1995, 43 (8), 1281). Milder conditions such as those described in S. L. Buchwald, J. Am., may also be used. Chem. Soc. 2002,124, 11 684.

[0044] A compound of the general formula (IV), for which B is a d-C6-alkyl group, can be converted to a compound of the general formula (IV) where B is a hydroxyl group, by the action of a base such as sodium hydroxide or potassium hydroxide in a solvent such as ethanol. A compound of general formula (IV) where B is a hydroxyl group can then be converted to a compound of general formula (IV) where B is a chlorine atom by the action of a chlorinating agent such as thionyl chloride in a solvent such as dichloromethane.

Compounds of the general formulas (I) and (VI) can then be obtained, for example, by reacting a compound of the general formula (IV) in which B is a chlorine atom, as obtained above, with an amine of the general formula (V), in which Z , Z 2 , Z 3 and Z 4 are as defined in the general formula (I), and W is a halogen atom, such as chlorine, bromine or iodine, with a cyclic amine Z as defined in of general formula (I), in a solvent such as dichloroethane, toluene or tetrahydrofuran. Compounds of the general formulas (I) and (VI) can also be obtained by reacting a compound of the general formula (IV) in which B is a hydroxyl group, as obtained above, with an amine of the general formula (V), in which Zi, Zz, Z3 and Z4 are as defined in the general formula (I) and W is a halogen atom, such as bromine or iodine, or with a cyclic amine Z as defined in the general formula (I), in the presence of an agent for coupling such as diethylcyanophosphonate, in the presence of a base such as triethylamine, in a solvent such as dimethylformamide, or in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, in the presence of N-1-hydroxybenzotyrazole, in a solvent such as dimethylformamide. When W is a halogen atom, compound (VI) is obtained. When W is a cyclic amine Z as defined in general formula (I), a compound of general formula (I) is obtained. A compound of the general formula (I) can also be obtained by reacting a compound of the general formula (VI) in which W is a halogen atom, in the presence of an amine of the formula ZH in which Z is a cyclic amine as defined in the general formula (I), without a solvent or in a solvent such as N-methylpyrrolidinone, or by applying the catalyzed N-arylation method as described in J. Hartwig (J. F. Hartwig, Angew Chem. Int. Ed. 2005, 44, 1371 - 1375), preferably in an inert atmosphere, in the presence of a base such as lithium bistrimethylsilylamide, in the presence of a catalytic amount of a palladium compound, such as palladium diacetate, and a catalytic amount of a palladium ligand, such as phosphine, all in a solvent solution such as dimethoxyethane (DME).

[0046] Compounds of the general formulas (I), (II) and (IV), in which X 1 , X 2 , X 3 i/or X 4 is a cyano group or aryl, can be obtained by a coupling reaction, catalyzed by a metal such as palladium, carried out on the corresponding compounds of the general formulas (I), (II) and (IV) in which X 1 f X 2 , X 3 i/or X 4 is a leaving group, for example, bromine, according to the methods described in literature or which are known to the average person skilled in the art. Compounds of the general formulas (I), (II) and (IV), in which Xi, X2, X3i/or X*, C(0)NR-|R2 are groups, can be obtained from the corresponding compounds of the general formulas (I), (II) and (IV) in which X-i, X2) is a X3i/or X4 cyano group, according to methods described in the literature or known to a person of ordinary skill. Compounds of general formulas (I), (II) and (IV), in which Xi, X2>X3, X4i/or R6, -S(0>alkyl or - S(0)2-alkyl group) can be obtained by oxidizing the corresponding compounds of formulas (I), (II) and (IV) in which X1tX2, X3iX4i/or R6, is a C-i-C6-thioalkyl group, according to methods described in the literature or known to the average person Similarly, compounds of the general formulas (I) and (IV), in which Y is substituted with an -S(O)-alkyl group, can be obtained by oxidation of the corresponding compounds of the formulas (I) and (IV) in which Y is substituted with a d-C6-thioalkyl group. Compounds of the general formula (I) in which Xi, X2, X3i/or X4 represents the corresponding C-R6 group C-OH group, can be obtained starting from the corresponding compounds of the general formula (I) in which Xi, X2, X3i/or X* is a C-R6 group corresponding to a C1-C6-alkyl group, according to methods described in the literature or known to a person skilled in the art.

[0047] Compounds of the general formulas (I), (II) and (IV), in which Xi, X2, X3i/or X4 are NR1R2, NR3COR4 or NR3SO2R5, can be obtained from the corresponding compounds of formulas (I), (II) and (IV) in which Xi, X2, X3i/or X» are a nitro group, for example, by reduction, followed by acylation or sulfonylation, according to methods described in the literature or which are known to a person skilled in the art. Compounds of the general formulas (I), (II) and (IV), in which X1 X2, X3i/or X4 is an NR1R2, NR3COR4 or NR3SO2R5 group, can be obtained from the corresponding compounds of the formulas (I), (II) and (IV) in which Xi, X2, X3i/or X* is, for example, a bromine atom, by coupling reaction with an amine, amide or sulfonamide, respectively, in the presence of a base, a phosphine and a base catalyst of palladium, according to methods described in the literature or known to a person of ordinary skill. Compounds of the general formulas (I), (II) and (IV), in which X 2 , X 3 i/or X 4 is an SC^NR^ group, can be obtained by a method similar to that described in Pharmazie 1990, 45, 346, or according to methods described in the literature or known to a person of ordinary skill.

Compounds of general formula (III) are commercially available and are described in the literature

(Carling R. W. et al J. Med. Chem. 2004 (47), 1807 -1822 or Russel M. G. N. et al. J. Med. Chem. 2005 (48), 1367 -1383) or are available using methods known to one of ordinary skill in the art. Some compounds of general formula (IV) are described in the literature (WO 07/010,144, for example). Compounds (V) and other reactants, when methods for their preparation are not described, can be purchased or are described in the literature (WO 05/028452, WO 02/048152, WO 06/040522, WO 04/052869, Heterocvcles 1977, 6(12), 1999 - 2004, J. Chem. Soc. Perkin trans 1, 1973 (1) 68 - 69, WO 05/035526, WO 04/062665, U.S. Pat. No. 4,104,385).

[0048] According to the following aspect, the subject of the invention are also compounds of formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg). These compounds are useful as intermediates for the synthesis of compounds of formula (I).

[0049] Amines of formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) can be obtained, for example, according to the process described in example no. 5, by aromatic nucleophilic substitution of the 6-chloropyridine precursor which is optionally substituted (Va: with a 5-methoxy group, Vb:

with a 4-methoxy group, Vd: with a 2-methyl group, Vg: with a 4-trifluoromethyl group), with an amine such as pyrrolidine, for example, in a solvent such as ethanol. Access to amines Va-g may then require reduction of the nitro group, for example, by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon, or any other methods known to one of ordinary skill in the art, to reduce the nitro group to an amine. Amines of formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) are obtained in the form of a powder or as an oil, in the form of a base or acid addition salt. Table 1 gives<1>H NMR data for these amines.

[050] The following examples describe the preparation of some compounds in accordance with the invention. These examples are not limiting and generally illustrative of the subject invention. The numbers of compounds given as examples correspond to those given in Table 2. Elemental microanalysis, LC-MS (liquid chromatography coupled to mass spectrometry) analyses, IR spectra or NMR spectra confirm the structures of the obtained compounds.

Example 1 (Compound No. 1)

N-{6-[((R)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]pyridin-3-yl}-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

1.1. 5-Fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid

[0051] An aqueous solution of sodium hydroxide, obtained from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 ml of water, was added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-

(3-fluorobenzyl)-1H-indole-2-carboxylate (W0 2006/024776) in 241 ml of ethanol. The mixture was heated for 2 hours and then concentrated under reduced pressure. The resulting solid was placed in 200 ml of water. The solution was washed twice with 100 ml of ethyl ether each, acidified by the successive addition of small amounts of concentrated hydrogen chloride.

acid, and then extracted with 200 ml of ethyl acetate. The organic phase was finally washed twice with 100 ml of water and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. After drying at 50 °C under reduced pressure, 6.4 g of the expected product was obtained, which will be used as such in the next step.

1.2 N-{6-[((R)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]pyridin-3-yl}-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 1)

[0052] 0.85 ml (4.91 mmol) of diisopropylethylamine was added, dropwise, at 20° C. in an argon atmosphere, to a solution of 0.47 g (1.64 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in step 1.1), 0.5 g (1.8 mmol) 3-amino-6-[((R)-3-tert-butoxycarbonylamino)pyrrolidin-1-ylpyridine (JP 2004175739) and 0.85 g (1.64 mmol) of trispyrrolidinophosphonium hexafluorophosphate (PYBOP) in 20 ml of dichloromethane. The mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and then taken up in 50 ml of ethyl acetate. This solution was then successively washed three times with 15 ml of saturated sodium hydrogen carbonate solution and with 20 ml of saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained product was purified by chromatography on a silica gel column, where the elution was carried out with a mixture of dichloromethane and methanol. The resulting solid was then triturated in ethyl ether. 0.788 g of solid substance was obtained, which was dried under reduced pressure.

Melting point: 207 - 20 °C.

<1>HNMR(DMSO D6 ), [δ] (ppm): 1.49 (s, 9 H); 1.85 (sext, 1 H); 2.1 (sext, 1 H); 3.2 (m, 4 H); 4.09 (m, 1 H); 5.88 (s, 2 H); 6.41 (d, 1H); 7.04 (m, 7 H); 7.61 (m, 2H); 7.8 (dxd, 1 H); 8.31 (d, 1 H); 10.19 (s, 1 H).

Example 2 (Compound No. 2)

N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

[0053] 0.28 ml (1.68 mmol) of diethyl cyanophosphonate was added, dropwise at 20 ° C, in an argon atmosphere, to a solution of 0.402 g (1.4 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.274 g (1.68 mmol) 3-amino-6-(pyrrolidin-1-yl)pyridine (WO 02/48152) in 10 ml of dry dimethylformamide. The mixture was stirred for 10 minutes and then 0.43 ml (3.08 mmol) of triethylamine was added dropwise. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and then taken up in 50 ml of ethyl acetate. This solution was then washed one after the other three times with 20 ml of saturated sodium hydrogen carbonate solution, 50 ml of water and 20 ml of saturated sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated in hot isopropyl ether. 0.527 g of solid substance was obtained, which was dried under reduced pressure.

Melting point: 199 - 201 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.9 (m, 4 H); 3.3 (m, 4 H); 5.82 (s, 2H); 6.4 (d, 1 H); 7.04 (m, 6 H); 7.51 (m, 2H); 7.77 (dxd, 1 H); 8.3 (d, 1 H); 10.25 (s, 1 H)

Example 3 (Compound No. 4)

N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

3.1 N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

23.8 ml (47.57 mmol) of a 2M solution of trimethylaluminum in toluene was added to a solution of 4.48 g (34.89 mmol) of 6-chloro-3-aminopyridine in 317 ml of toluene, stirred at 20° C. under an argon atmosphere. The solution was then heated to 120 °C and 10 g (31.71 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO 2006/024776) were added in several steps. The reaction mixture was refluxed for 4 hours and then cooled to 0 °C. 15 ml of water was added to the reaction medium, and then it was extracted twice with

per 200 ml of ethyl acetate. The organic phases were combined and washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was triturated in 100 ml of ethyl ether, the product was filtered, and 10 g of the expected product was obtained in powder form.

<1>H NMR (DMSO D6 ), [6] (ppm): 5.9 (s, 2 H); 6.9 (m, 2H); 7.05 (txd, 1H); 7.2 (txd, 1 H); 7.32 (m, 1 H); 7.58 (m, 4H); 8.25 (d, 1 H); 8.79 (s, 1 H); 10.79 (s, 1 H)

3.2. N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

(Compound No. 4)

[0055] 4.2 ml (4.2 mmol) of a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran was added to a mixture, stirred at 0 °C under an argon atmosphere, of 0.7 g (1.76 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide obtained in step 3.1. 0.123 g (2.11 mmol) azetidine, 8 mg (0.04 mmol) palladium diacetate and 19.5 mg (0.04 mmol) (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-tert-butylphosphine in 1.8 ml of dry and degassed dimethoxyethane. The reactor was sealed and then heated to 100 °C for 16 hours. The reaction mixture was then poured into 50 ml of water. 5 ml of a molar solution of hydrochloric acid and then 50 ml of a saturated solution of sodium hydrogen carbonate were slowly added. The mixture was extracted twice with 50 ml of ethyl acetate. The organic phases were combined and then washed twice with 50 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained product was purified by chromatography on a silica gel column, where the elution was carried out with a mixture of dichloromethane and acetone. The resulting solid was then triturated in 20 ml of hot isopropanol, separated by filtration, and then recrystallized from a mixture of ethanol and methanol. After filtration and drying under reduced pressure, 0.31 g of solid was obtained.

Melting point: 227 - 228 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.25 (pent, 2 H); 3.9 (t, 4H); 6.01 (s, 2 H); 6.35 (d, 1 H); 6.89 (m, 2 H); 7.01 (txd, 1 H); 7.12 (txd, 1 H); 7.19 (q, 1 H); 7.34 (s, 1 H); 7.52 (m, 2 H); 7.82 (dxd, 1 H); 8.31 (s, 1 H); 10.28 (s, 1 H).

Example 4 (Compound No. 7)

N-[6-(3-Hydroxypyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

[0056] A mixture of 0.4 g (1.01 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, obtained in step 3.1, and 0.81 ml (10.06 mmol) of 3-hydroxypyrrolidine in 1.2 ml of N-methylpyrrolidinone was heated for 20 minutes in a microwave oven. regulated at 200 °C and 300 watts. The reaction mixture was then poured into 50 ml of water. The solid substance was separated by filtration and purified by chromatography on a silica gel column, where the elution was carried out with a mixture of dichloromethane and methanol. The resulting solid was then recrystallized from a mixture of methanol and dichloromethane. Filtration and drying under reduced pressure yielded 0.22 g of solid substance.

Melting point: 229 - 230 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.9 (m, 1 H); 2.04 (m, 1 H); 3.3 - 3.47 (m, 4H); 4.49 (s, 1 H); 4.92 (s, 1 H); 5.9 (s, 2 H); 6.47 (d, 1 H); 6.91 (m, 2 H); 7.05 (txd, 1 H); 7.12 (txd, 1 H); 7.31 (q, 1 H); 7.39 (s, 1 H); 7.55 (m, 2 H); 7.82 (dxd, 1 H); 8.37 (s, 1 H); 10.22 (s, 1

H).

Example 5 (Compound No. 8)

N-[5-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

5.1 3-Methoxy-5-nitro-2-(pyrrolidin-1-yl)pyridine

[0057] A solution of 3 g (15.91 mmol) of 2-chloro-3-methoxy-5-nitropyridine and 2 ml (23.86 mmol) of pyrrolidine in 30 ml of dimethylformamide was heated at 100 °C for 4 hours. The reaction mixture was then concentrated under reduced pressure and then poured into 100 ml of water and extracted three times with 100 ml of ethyl acetate each. The organic phases were combined, washed twice with 50 ml of water and then once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. 3.47 g of the expected product in the form of an orange powder was isolated. <1>H NMR (DMSO D6 ), [δ] (ppm): 1.9 (m, 4 H); 3.79 (m, 4H); 3.88 (s, 3 H); 7.62 (s, 1 H); 8.69 (s, 1 H).

5.2 3-Methoxy-2-(pyrrolidin-1-yl)-4-aminopyridine (Compound Va)

[0058] A suspension of 3.4 g (15.54 mmol) of 3-methoxy-5-nitro-2-(pyrrolidin-1-yl)pyridine, obtained in step 5.1, and 0.33 g of 10% palladium by weight in 40 ml of ethanol was stirred at 20 °C for 5 hours under a pressure of 5.6 bar of hydrogen. The reaction mixture was then filtered through celite, concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with a mixture of dichloromethane and methanol. Thus, 0.9 g of the expected product was isolated, which will be used as such in the further course of the synthesis. <1>H NMR (CDCl3), [δ] (ppm): 2.5 (m, 4 H); 3.23 (broad peak, 2 H); 3.49 (m, 4H); 3.91 (s, 3H); 5.90 (s, 1H); 7.71 (s, 1 H).

5.3 N-[5-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 8)

A solution of 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, obtained in step 1.1, 0.33 g (1.74 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 0.23 g (1.74 mmol) of N-1-hydroxybenzotriazole in 10 ml.

of dimethylformamide was stirred for 15 minutes at 20 °C. 0.43 g (2.26 mmol) of compound (Va) obtained in step 5.2 was then added to the reaction medium. The reaction mixture was then stirred for 12 hours at 20 °C and concentrated under reduced pressure, poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate. The organic phases were combined, then washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under

reduced pressure. The obtained product was purified by chromatography on a silk gel column, eluting with a mixture of dichloromethane and methanol. 0.3 g of the expected product was isolated.

Melting point: 172-174 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.85 (m, 4 H); 3.61 (m, 4 H); 3.78 (s, 3H); 5.91 (s, 2 H); 6.91 (m, 2 H); 7.07 (txd, 1 H); 7.15 (txd, 1 H); 7.31 (q, 1 H); 7.4 (s, 1 H); 7.58 (m, 3H); 8.08 (s, 1 H); 10.3 (s, 1 H).

Example 6 (Compound No. 16)

N-[4-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

6.1 4-Methoxy-5-nitro-2-(pyrrolidin-1-yl)pyridine

[0060] The process was carried out according to the method described in step 5.1, using 5.4 g (28.64 mmol) of 2-chloro-4-methoxy-5-nitropyridine (WO 03/080610) and 4.53 g (63 mmol) of pyrrolidine. In this case, the obtained product was purified by chromatography on a silica gel column, where the elution was carried out with a mixture of heptane and ethyl acetate. Thus, 3 g of the expected product was isolated. <1>H NMR (DMSO D6 ), [δ] (ppm): 2.17 (m, 4 H); 3.65 (m, 4 H); 4.07 (s, 3 H); 5.79 (s, 1 H); 8.98 (s, 1 H).

6.2 4-Methoxy-2-(pyrrolidin-1-yl)-5-aminopyridine (Compound Vb)

[0061] The process was carried out according to the method described in step 5.2, using 1.5 g (6.72 mmol) of 4-methoxy-5-nitro-2-(pyrrolidin-1-yl)pyridine, obtained in step 6.1, and 0.15 g of 10% palladium on charcoal. Thus, 1.25 g of the expected product was obtained. <1>H NMR (DMSO D6 ), [δ] (ppm): 1.81 (m, 4 H); 3.29 (m, 4H); 3.71 (s, 3H); 4.52 (broad peak, 2 H); 6.61 (s, 1 H); 7.16 (s, 1 H).

6.3 N-[4-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 16)

[0062] The process was carried out according to the method described in example 2, using 2, 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.424 g (2.09 mmol) of 4-methoxy-2-(pyrrolidin-1-yl)-5-aminopyridine, obtained in step 6.1. (Compound Vb). Thus, 0.59 g of the expected product was isolated,

Melting point: 196 - 198 [deg.] C.

<1>H NMR (CDCl3), [5] (ppm): 2.01 (m, 4 H); 3.49 (m, 4H); 3.91 (s, 3H); 5.86 (m, 3H); 6.79 (dxd 1 H); 6.9 (m, 2 H); 7.02 (m, 2 H); 7.23 (m, 2 H); 7.34 (dxd, 1 H); 7.9 (m, 1 H); 8.85 (s, 1 H).

Example 7 (Compound No. 20)

N-[6-(1-Oxypyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

A solution of 0.5 g (1.16 mmol) of N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (compound no. 2 obtained according to the method described in example 2) and 0.31 g (1.27 mmol) of methachloroperbenzoic acid (70%) in 20 ml of dichloromethane. was stirred at 20 °C for 24 hours. 100 ml of dichloromethane was added to the reaction mixture, then it was washed one after the other with 20 ml of saturated sodium carbonate solution and then 3 times with 20 ml of water each, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product was then purified by chromatography on a silica gel column, where the elution was carried out with a mixture of dichloromethane and methanol. Thus, 0.23 g of the expected product was isolated.

Melting point: 140 - 143<0>C.

<*>H NMR (DMSO D6 ), [δ] (ppm): 2.1 (m, 2 H); 2.35 (m, 2 H); 3.31 (m, 2 H); 4.08 (m, 2 H); 5.91 (s, 2 H); 6.9 (m, 2 H); 7.04 (txd, 1 H); 7.2 (txd, 1 H); 7.32 (m, 1 H); 7.51 (s, 1 H); 7.62 (m, 2H); 8.41 (m, 2 H); 8.8 (s, 1 H); 10.91 (s, 1 H)

Example 8 (Compound No. 21)

N-[2-(PyroHdin-1-yl)pyrimidin-5-yl]-5-fluoro-1-(3-fluorobenzyl)^H-indole-2-carboxamide

[0064] The process was carried out according to the method described in example 2, using 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 2-(pyrrolidin-1-yl)-5-aminopyrimidine (US 20060281772).

Melting point: 220 - 222 °C.

<1>H NMR (DMSO D6 ), [5] (ppm); 1.97 (m, 4 H); 3.51 (m, 4 H); 5.89 (s, 2H); 6.91 (m, 2 H); 7.05 (txd, 1 H); 7.16 (txd, 1 H); 7.31 (m, 1 H); 7.40 (s, 1 H); 7.57 (m, 2H); 8.61 (s, 2 H); 10.32 (s, 1 H).

Example 9 (Compound No. 27)

N-[2-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide 9.1 2-Methyl-6-(pyrrolidin-1-yl)-3-nitropyridine

A suspension of 0.5 g (2.9 mmol) 6-chloro-3-nitro-2-picoline, 0.73 ml (8.69 mmol) pyrrolidine and 0.8 g (5.79 mmol) potassium carbonate was heated at 110 °C for 2 hours.

The reaction mixture was then concentrated under reduced pressure and poured into 100 ml of water. The solid substance was separated by filtration and dried, so that 0.55 g of the expected product was obtained in the form of a yellow solid substance which will be used as such in the further course of the synthesis.

9.2 2-Methyl-6-{pyrrolidin-1-yl)-3-aminopyridine (Compound No. Vd)

[0066] The process was carried out according to the method described in step 5.2, using 0.55 g (2.65 mmol) of 2-methyl-6-(pyrrolidin-1-yl)-3-nitropyridine, obtained in step 9.1, and 0.1 g of 10% palladium on carbon. Thus, 0.34 g of the expected product was obtained, which will be used as such in the further course of the synthesis.

<1>H NMR (CDCl3), [6] (ppm): 1.89 (m, 4 H); 2.23 (s, 3 H); 2.98 (wide s, 2 H); 3.31 (m, 4 H);

6.03 (d, 1 H); 6.82 (d, 1 H).

9.3 N-[2-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 27)

The process was carried out according to the method described in example 5.3, using 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.32 g (1.81 mmol) of 2-methyl-6-(pyrrolidin-1-yl)-3-aminopyridine (compound no. Vd), described in step 9.2. In this way, 0.3 g of the expected product was isolated.

Melting point: 213-214 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.92 (m, 4 H); 2.21 (s, 3 H); 3.49 (m, 4H); 5.88 (s, 2H); 6.29 (d, 1 H); 6.87 (d, 1H); 6.92 (d, 1H); 7.05 (txd, 1 H); 7.15 (txd, 1 H); 7.38 (m, 2 H); 7.39 (s, 1 H); 7.52 (d, 1 H); 7.67 (m, 1 H); 9.91 (s, 1 H).

Example 10 (Compound No. 24)

N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

10.1 2-(3-Hydroxyazetidin-1-yl)-5-nitropyridine

[0068] The process was carried out according to the method described in step 5.1, using 7 g (42.83 mmol) of 2-chloro-5-nitropyridine and 5.75 g (51.4 mmol) of 3-azetidinol hydrochloride. In this case, 13 g (128.45 mmol) of triethylamine was also added. Thus, 8 g of the expected product was isolated.

Melting point: 175-176 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 3.85 (m, 2 H); 4.36 (m, 2 H); 4.62 (m, 1 H); 5.88 (d, 1 H); 6.4 (d, 1 H); 8.18 (dxd, 1 H); 8.92 (s, 1 H).

10.2 2-(3-Hydroxyazetidin-1-yl)-5-aminopyridine (Compound Ve)

[0069] The process was carried out according to the method described in step 5.2, using 5.5 g (28.18 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, obtained in step 10.1, and 0.5 g of 10% palladium on carbon. Thus, 4.5 g of the expected product was obtained in the form of purple crystals.

Melting point: 148-150 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 3.49 (m, 2 H); 3.98 (m, 2 H); 4.48 (broad peak, 3 H); 5.48 (broad peak, 1 H); 6.22 (d, 1 H); 6.91 (d, 1 H); 7.58 (s, 1 H).

10.3 N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 24)

[0070] The process was carried out according to the method described in example 2, using 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (Example 1.1) and 0.35 g (2.09 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, obtained in step 10.2 (Compound Ve).

Melting point: 199 - 200 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 3.67 (m, 2 H); 4.13 (m, 2 H); 4.58 (m, 1 H); 5.61 (m, 1 H); 5.91 (s, 2H); 6.42 (d, 1 H); 6.91 (m, 2 H); 7.05 (m, 1 H); 7.18 (txd, 1 H); 7.36 (m, 1 H); 7.42 (s, 1 H); 7.58 (m, 2 H); 7.88 (dxd, 1H); 8.39 (s, 1 H); 10.35 (s, 1 H).

Example 11 (Compound No. 53)

N-[6-(Pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

11.1 Methyl 6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylate

[0071] A mixture of 2.5 g (10.43 mmol) of methyl 6-chloro-4-trifluoromethylnicotinate, 2.88 g (20.87 mmol) of potassium carbonate and 2.61 ml (31.3 mmol) of pyrrolidine in 90 ml of dimethylformamide was heated to 100 °C. during 3 hours. The reaction mixture was then concentrated under reduced pressure and taken up in 100 ml of water. The precipitate was separated by filtration and washed with 150 ml of water. After drying under reduced pressure, 2.5 g of the expected product was isolated. <1>H NMR (CDCl3), [δ] (ppm): 2.11 (m, 4 H); 3.61 (broad peak, 4 H); 3.93 (s, 3 H); 6.69 (s, 1 H); 8.89 (s, 1 H).

11.2 6-(Pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylic acid

[0072] A mixture of 2.5 g (9.12 mmol) of methyl 6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylate, obtained in step 11.1, and 0.76 g (13.67 mmol) of potassium hydroxide in 50 ml of methanol and 2 ml of water was stirred for 24 hours at 20 °C. The mixture was then concentrated under reduced pressure. Then 100 ml of water was added and the solution was washed with 100 ml of dichloromethane and then acidified to pH 4 by adding concentrated hydrochloric acid. The precipitate was separated by filtration and washed with 50 ml of water. After drying under reduced pressure, 2.2 g of the expected product was isolated. <1>H NMR (DMSO D6 ), [δ] (ppm): 1.99 (s, 4 H); 3.51 (broad peak, 4 H); 6.71 (s, 1 H); 8.72 (s, 1 H).

11.3 6-(Pyrrolidin-1-yl)-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine

[0073] A mixture of 2.2 g (8.45 mmol) of 6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylic acid, obtained in step 11.2, 2.37 ml (10.99 mmol) of diphenylphosphorylazide and 2.95 ml (21.14 mmol) of triethylamine in 25 ml of tert-butanol was heated for 5 hours at 90 °C. The reaction mixture was then concentrated under reduced pressure, taken up in 50 ml of water, and extracted 3 times with 50 ml of dichloromethane each. The organic phases were combined, washed with 50 ml of water, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained oil was purified by column chromatography on silk gel, where the elution was carried out with a mixture of dichloromethane and methanol. Thus, 1.05 g of the expected product was isolated. <1>H NMR (CDCl3), [6] (ppm): 1.53 (s, 9 H); 2.09 (m, 4 H); 3.51 (m, 4 H); 6.2 (broad peak, 1 H); 6.52 (s, 1 H); 8.39 (broad peak, 1H).

11.4 6-(Pyrrolidin-1-ii)-4-trifluoromethyl-3-aminopyridine hydrochloride (Amine Vg)

[0074] A solution of 1 g (3.02 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine, obtained in step 11.3, in 11 ml of 4N hydrochloric acid in dioxane was stirred for 5 hours at reflux. Then, 200 ml of ethyl ether was added to the cooled reaction mixture. 0.8 g of precipitate was separated by filtration.

Melting point: 207 - 209 °C;

<1>H NMR (DMSO D6 ), [δ] (ppm): 2 (m, 4 H); 3.52 (m, 4 H); 7.1 (s, 1 H); 7.49 (broad peak, 2 H); 7.92 (s, 1 H).

11.5 N-[6-(Pyrrolidin-1-yl)-4-trifluoromethylpyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 53)

The process was carried out according to the method described in step 5.3, using 0.3 g (1.04 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1), and 0.363 g (1.36 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-aminopyridine hydrochloride, obtained in step 11.4, in the presence of 0.22 ml (1.57 mmol) of triethylamine.

Melting point: 170 - 171 °C;

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.99 (m, 4 H); 3.49 (m, 4H); 5.87 (s, 2 H); 6.7 (s, 1 H); 6.86 - 7.22 (m, 4H); 7.31 (m, 1 H); 7.4 (s, 1 H); 7.57 (dxd, 1 H); 7.65 (m, 1 H); 8.11 (s, 1

H).

Example 12 (Compound No. 12)

N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1 H -indole-2-carboxamide

12.1 2-(3-Azabicyclo[3.1.0]hex-3-yl)-5-nitropyridine

[0076] A suspension of 0.2 g (1.26 mmol) of 2-chloro-5-nitropyridine, 0.166 g (1.39 mmol) of 3-azabicyclo[3.1.0]hexane (Bioorg. & Med. Chem. Lett. 2005, 15(8) 2093) and 0.52 g (3.78 mmol) of potassium carbonate in 5 ml of dimethylformamide. was stirred at room temperature for 36 hours. The mixture was then poured into 5 ml of water and extracted 3 times with 20 ml of ethyl acetate each. The organic phases were then combined, dried over magnesium sulfate, and concentrated under reduced pressure. Thus, 0.22 g of the expected product was obtained, which was used as such in the further course of the synthesis.

12.2 2-(3-Azabicyclo[3.1.0]hex-3-yl)-5-aminopyridine (Vf)

[0077] The process was carried out according to the method described in step 5.2, using 0.2 g (0.97 mol) of 2-(3-azabicyclo[3.1.0]hex-3-yl)-5-nitropyridine, described in step 12.1, and 0.5 g of 10% palladium on carbon. Thus, 0.1 g of the expected product was isolated, which will be used in the next step. <1>H NMR (DMSO D6 ), [δ] (ppm): 0.2 (m, 1 H); 0.66 (m, 1 H); 1.6 (m, 2 H); 3.11 (m, 2 H); 3.51 (d, 2 H); 4.32 (broad peak, 2 H); 6.25 (d, 1 H); 6.99 (d, 1 H); 7.55 (s, 1 H).

12.3 N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide (Compound No. 28).

The process was carried out according to the method described in example 2, using 0.15 g (0.52 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 0.1 g (0.57 mmol) of 2-(3-azabicyclo[3.1.0]hex-3-yl)-5-aminopyridine, obtained in step 12.2. Thus, 0.17 g of the expected product was isolated.

Melting point: 193-195 °C.

<1>H NMR (DMSO D6 ), [h] (ppm): 0.02 (m, 1 H); 0.51 (m, 1 H); 1.47 (m, 2 H); 3.41 (d, 2H); 5.67 (s, 2H); 6.25 (d, 1 H); 6.69 (m, 2 H); 6.83 (m, 1 H); 6.93 (m, 1 H); 7.1 (m, 1 H); 7.15 (s, 1 H); 7.31 (dxd, 1 H); 7.39 (m, 1H); 7.6 (m, 1 H); 8.11 (s, 1 H); 10.03 (s, 1 H).

Example 13 (Compound No. 29)

N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]- 1-(3-fluorobenzyl)-5-trifluoromethyl-1H-indole-2-carboxamide

[0079] The process was carried out according to the method described in example 2, using 5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736) and 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, obtained in step 10.2 of example 10 (Compound Ve). Melting point: 194 - 196 °C. <1>H NMR (DMSO D6 ), [6] (ppm): 3.68 (m, 2 H); 4.17 (m, 2 H); 4.59 (m, 1 H); 5.6 (d, 1 H); 5.93 (s, 2 H); 6.42 (d, 1 H); 6.91 (m, 2 H); 7.09 (txd, 1 H); 7.32 (m, 1 H); 7.55 (m, 2 H); 7.79 (d, 1 H); 7.88 (d, 1 H); 8.2 (s, 1 H); 8.38 (s, 1 H); 10.41 (s, 1 H).

Example 14 (Compound No. 30)

N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-fluorobenzyl)-6-trifluoromethyl-1H-indole-2-carboxamide

[0080] The process was carried out according to the method described in example 2, using 6-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, obtained in step 10.2 of example 10 (Compound Ve).

Melting point: 253 - 255 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 3.67 (m, 2 H); 4.17 (m, 2 H); 4.59 (m, 1 H); 5.6 (d, 1 H); 6.0 (s, 2 H); 6.42 (d, 1 H); 6.91 (m, 2 H); 7.09 (txd, 1 H); 7.36 (m, 1 H); 7.47 (d, 1 H); 7.51 (s, 1 H); 7.85 (d, 1H); 7.99 (d, 1 H); 8.06 (s, 1 H); 8.33 (s, 1 H); 10.41 (s, 1 H).

Example 15 (Compound No. 23)

N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-fluoro-1H-indol-2-carboxamide

15.1 5-Fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid

[0081] A solution of 2.1 g (7.04 mmol) of ethyl 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate (WO 2007/010144) and 1.18 g (21.12 mmol) of potassium hydroxide in 80 ml of ethanol and 2 ml of water was refluxed for 2 hours. The reaction mixture was then concentrated under reduced pressure. 100 ml of water was added and the pH of the solution was adjusted to pH 8 by the addition of a concentrated solution of hydrochloric acid. A precipitate was obtained by filtration, which was washed with water and then dried under reduced pressure. Thus, 1.5 g of the expected product was obtained.

Melting point: 282 - 283 °C.

15.2 N-[6-Chloropyridin-3-yl]-5-fluoro-1-[(pyridin-4-yl)methyl]-1 H-indol-2-carboxamide

The process was carried out according to the method described in example 2, using 0.7 g (2.59 mmol) of 5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid, obtained in step 15.1, and 0.4 g (3.11 mmol) of 2-chloro-5-aminopyridine. 0.41 g of the expected product was isolated.

Melting point: 244 - 246 °C.

15.3 N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-fluoro-1H-indol-2-carboxamide

(Compound No. 23)

[0083] The process was performed according to the method described in example 2, using 0.4 g (1.05 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxamide, obtained in step 15.2, and 2.63 ml (31.51 mmol) of pyrrolidine. 0.24 g of the expected product was isolated.

Melting point: 255 - 257 °C.

<1>H NMR (DMSO D6 ), [h] (ppm): 1.92 (m, 4 H); 3.38 (m, 2 H); 5.92 (s, 4 H); 6.45 (d, 1 H); 7.0 (d, 2 H); 7.16 (txd, 1 H); 7.43 (s, 1 H); 7.57 (m, 2 H); 7.81 (m, 1 H); 8.31 (s, 1 H); 8.48 (d, 2H); 10.22 (s, 1 H).

Example 16 (Compound No. 14)

N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]- 5-trifluoromethyl-1H-indole-2-carboxamide 16.1 5-Trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid

[0084] The process was carried out according to the method described in example 15.1, using ethyl 5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylate (WO 07/010,144). The product was used as such in the further course of the synthesis.

16.2 N-[6-Chloropyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-indole-2-carboxamide

[0085] The process was performed according to the method described in example 3.1, using 0.5 g (1.56 mmol) of 5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid, obtained in step 16.1, and 0.22 g (1.72 mmol) of 2-chloro-5-aminopyridine. Using this method, 0.5 g of the expected product was isolated, which was used as such in the further course of the synthesis.

16.3 N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-indole-2-carboxamide (Compound No. 14)

[0086] The process was carried out according to the method described in example 4, using 0.5 g (1.16 mmol) of N-[6-chloropyridin-3-yl]-1-[(pyridin-4-yl)methyl]-5-trifluoromethyl-1H-indole-2-carboxamide, obtained in step 16.2, and 2.91 ml (34.82 mmol) of pyrrolidine. The mixture was placed in a pressure tube which was heated for 50 minutes at 170 °C in a microwave oven at 200 watts. The mixture was then concentrated under reduced pressure, and taken up in 100 ml of ethyl acetate. The organic phase was then washed twice with 30 ml of water and once with saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained product was purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol. Thus, 0.24 g of the expected product was isolated.

Melting point: 248 - 250 °C.

<1>H NMR (DMSO D6 ), [6] (ppm): 1.95 (m, 4 H); 3.41 (m, 4H); 5.98 (s, 2H); 6.45 (d, 1 H); 7.03 (d, 2 H); 7.59 (m, 2 H); 7.73 (d, 1 H); 7.81 (d, 1 H); 8.19 (s, 1 H); 8.32 (s, 1 H); 8.49 (d, 2H).

Example 17 (Compound No. 22)

N-[6-(3-Azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

[0087] A mixture of 0.2 g (0.5 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, obtained in step 3.1, 0.0806 g (0.6 mmol) of 3-azabicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 0.0564 g (1.01 mmol) of potassium hydroxide in 0.5 ml of N-methylpyrrolidinone was heated for 90 minutes in a microwave oven regulated at 150 °C and 150 watts. The reaction mixture was then poured into 20 ml of water. The mixture was extracted three times with 30 ml each of ethyl acetate. The combined organic phases were washed with 30 ml of water, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting solid was then purified by chromatography on a silica gel column, eluting with a mixture of n-heptane and ethyl acetate. Thus, 35 mg of the expected product was isolated.

Melting point: 163-165 °C.

<1>H NMR (DMSO D6 ), [δ] (ppm): 1.71 (m, 2 H); 2.23 (m, 2H); 3.02 (m, 2 H); 3.2 (m, 2 H); 3.63 (d, 2 H); 5.9 (s, 2 H); 6.62 (d, 1 H); 6.91 (m, 2 H); 7.05 (txd, 1 H); 7.16 (txd, 1 H); 7.33 (m, 1 H); 7.4 (s, 1 H); 7.54 (dxd, 1 H); 7.6 (m, 1 H); 7.88 (dxd, 1 H); 8.4 (s, 1 H); 10.3 (s, 1 H).

[0088] Table 2 below illustrates the chemical structures and physical properties of some compounds of general formula (I) according to the invention.

In this table:

- "T.t." the column gives the melting points of the product in degrees Celsius (°C); - in the "salt/base" column, "-" represents the compound in the form of a free base, while "HCI" represents the compound in the form of hydrochloride and the ratio in parentheses is the ratio (acid/base); "t-Bu" corresponds to the tert-butyl group, "iPr" to the isopropyl group, "et" to the ethyl group.

[0089] As an example, the NMR data of some compounds from this table are given.

Compound No. 25:

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.31 (m, 2 H); 3.92 (t, 4H); 5.92 (s, 2H); 6.4 (d, 1 H); 6.94 (m, 2 H); 7.09 (txd, 1 H); 7.37 (m, 1 H); 7.57 (m, 2H); 7.79 (d, 1 H); 7.87 (dxd, 1 H); 8.2 (s, 1 H); 8.36 (d, 2H); 10.41 (s, 1 H).

Compound No. 26:

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.32 (m, 2 H); 3.92 (t, 4H); 5.91 (s, 2 H); 6.38 (d, 1 H); 6.99 (d, 2 H); 7.15 (txd, 1 H); 7.41 (s, 1 H); 7.57 (m, 2 H); 7.81 (m, 1 H); 8.43 (m, 1 H); 8.46 (d, 2 H); 10.4 (s, 1 H).

Compound No. 35:

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.32 (m, 2 H); 3.21 (s, 3 H); 3.92 (t, 4H); 5.98 (s, 2H); 6.4 (d, 1 H); 6.92 (d, 2 H); 7.09 (txd, 1 H); 7.35 (m, 1 H); 7.6 (s, 1 H); 7.81 (m, 3 H); 8.39 (m, 2 H); 10.42 (s, 1 H).

Compound No. 38:

<1>H NMR (DMSO D6 ), [6] (ppm): 2.31 (m, 2 H); 3.92 (t, 4H); 5.92 (s, 2H); 6.4 (d, 1 H); 6.93 (m, 3H); 7.08 (txd, 1 H); 7.31 (m, 2 H); 7.41 (m, 1 H); 7.61 (s, 1 H); 7.86 (dxd, 1H); 8.38 (s, 1 H); 10.3 (s, 1 H).

Compound No. 40:

<1>H NMR (DMSO D6 ), [h] (ppm): 2.31 (m, 2 H); 3.90 (t, 4 H); 5.89 (s, 2 H); 6.4 (d, 1 H); 6.91 (m, 2H); 7.06 (m, 2 H); 7.33 (m, 1 H); 7.41 (s, 1 H); 7.47 (dxd, 1 H); 7.78 (m, 1 H); 7.86 (m, 1 H); 8.35 (s, 1 H); 10.23 (s, 1 H).

Compound No. 45:

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.31 (m, 2 ); 2.56 (s, 3); 3.91 (t, 4); 5.9 (s, 2); 6.4 (d, 1); 6.91 (m, H); 7.04 (txd, 1 ); 7.18 (m, 1); 7.31 (m, 2); 7.49 (s, 1); 7.88 (m, 1); 8.38 (s, 1); 10.25 (s, 1).

Compound No. 46:

<1>H NMR (DMSO D6 ), [6] (ppm): 2.31 (m, 2 ); 2.41 (s, 3); 3.91 (t, 4); 5.85 (s, 2);

6.4 (d, 1); 6.82 - 7.09 (m, 4 H); 7.35 (m, 3 H); 7.61 (d, 1 H); 7.83 (dxd, 1 H);

8.36 (s, 1 H); 10.21 (s, 1 H).

Compound No. 47:

<1>H NMR (DMSO D6 ), [6] (ppm): 2.29 (m, 2 H); 2.4 (s, 3 H); 3.91 (t, 4H); 5.89 (s, 2 H); 6.39 (d, 1 H); 6.82 - 6.91 (m, 2H); 7.02 (txd, 1 H); 7.12 (dxd, 1 H); 7.31 (m, 2 H); 7.41 (d, 1 H); 7.51 (s, 1 H); 7.87 (dxd, 1 H); 8.34 (s, 1 H); 10.23 (s, 1 H).

Compound No. 49:

<1>NMR (DMSO D6 ), [5] (ppm): 1.32 (s, 9 ); 2.3 (m, 2); 3.91 (t, 4); 5.85 (s, 2);

6.38 (d, 1); 6.92 (m, 2); 7.03 (txd, 1 ); 7.35 (m, 4); 7.66 (s, 1); 7.85 (dxd, 1);

8.43 (s, 1); 10.19 (s, 1).

Compound No. 52:

<1>H NMR (DMSO D6 ), [δ] (ppm): 2.31 (m, 2 ); 3.91 (t, 4); 6 (s, 2); 6.39 (d, 1);

6.91 (m, 2); 7.07 (txd, 1 ); 7.32 (m, 1); 7.45 (d, 1); 7.49 (s, 1); 7.82 (dxd, 1);

7.92 (d, 1); 8.02 (s, 1); 8.34 (s, 1); 10.41 (s, 1).

[0090] The compounds of the present invention have been subjected to pharmacological tests in vitro and in vivo, which have shown that they are of interest as substances with therapeutic activities.

[0091] The compounds of the invention also have the characteristic of solubility in water which ensures good activity in vivo.

Capsaicin-induced current inhibition assay in rat DRG

[0092] - Primary cell culture of dorsal root ganglia (DRG, from rachis dorsala) of rats:

DRG neurons naturally express the TRPV1 receptor.

Primary neonatal rat DRG cultures are obtained from 1-day-old rat pups. Briefly, after dissection, ganglia are trypsinized and cells are mechanically dissociated by menagee trituration. Cells are resuspended in basic Eagle's culture medium containing 10% fetal bovine serum, 25 mM KCl, 2 mM glutamine, 100 µg/mL gentamicin, and 50 ng/mL NGF, then plated on laminin-coated glass slides (0.25 x 10<6> cells per slide) which are then placed in 12-well Corning chambers. Cells are incubated at 37 °C in a humidified atmosphere with 5% CO 2 and 95% air. After 48 hours, cytosine B-D-arabinoside (1 µM) was added to the culture to prevent the development of non-neuronal cells. Plates are transferred to experimental chambers for patch-clamp testing after 7-10 days

Electrophysiology:

Measuring chambers (volume 800 µl), containing the cell preparation, were placed under an inverted microscope (Olvmpus IMT2) with Hoffman optics (Modulation Contrast, New York) and observed under 400x magnification. Chambers were continuously perfused under the influence of gravity (2.5 mL/min) using a solution distributor with 8 inlets, the only outlet of which was a polyethylene tube (opening 500 pm) placed at least 3 mm from the examined cell. A "whole cell" configuration of the patch-clamp technique was used. Borosilicate glass pipettes (resistance 5-10 MΩ) are approached to the cell using a 3D piezoelectric micromanipulator (Burleigh, PC1000). Total current (membrane potential was fixed at −60 mV) was recorded with an Axopatch 1D amplifier (Axon Instruments, Foster City, CA), connected to a PC controlled by the Pclamp8 program (Axon Instrument). The current traces are registered on paper and simultaneously digitized (calibration frequency is from 15 to 25 Hz) and registered on the hard disk of the PC.

Application of a micromolar solution of capsaicin induces in DRG cells (voltage fixed at -70 mV) a cationic inward current. To minimize receptor desensitization, intervals of at least one minute were maintained between two capsaicin administrations. After a control period (stabilization of the response to capsaicin alone), the test compounds of the present invention were administered, alone, at certain concentrations (10 nM or 1 nM concentration) for 4 to 5 minutes, during which time several "capsaicin + compound" tests were performed (obtaining maximal inhibition). The results are expressed in percent inhibition of the control response to capsaicin.

[0093] Percentages of inhibition of the response to capsaicin (1 µM) are between 20% and 100% for the most active compounds of the invention which were tested at concentrations from 10 nM to 0.1 nM (see examples in Table 3).

Pronal compounds are, therefore, effective in vitro antagonists of TRPVI-type receptors

Mouse corneal irritation test

[0094] The irritating nature of capsaicin can easily be determined at the level of the cornea, since this organ is one of those most animated by C fibers. In this context, according to preliminary experiments, the application of a very small amount of capsaicin (2 ul at a concentration of 160 uM) to the corneal surface of the animal leads to a certain number of stereotyped behaviors associated with irritation and this can be easily registered. Among these are blinking the eye, rubbing the watery eye with the ipsilateral front paw, rubbing the face with both front legs, scratching the same side of the face with the hind leg. The duration of this behavior does not exceed 2 minutes and the animal then returns to its normal activity. Her appearance is also normal. A mouse doesn't hide in a corner with its hair on end And it doesn't show any visible signs of suffering. From this it can be concluded that the duration of action of capsaicin is less than 2 minutes.

Brief overview of the methodology:

[0095] The principle of the series of experiments is to determine whether the compounds of the invention can influence behavior in response to a given amount of capsaicin. Capsaicin was initially diluted to 25 mM in DMSO and diluted for final use in physiological saline with 10% Tween 80. It appears, based on control tests, that, under these conditions, the solvent has no effect. 500 µM, was administered by topical application to the corneal surface in a volume of 2 µl, 10 minutes before capsaicin application. 2 µl of 160 µM capsaicin prepared as indicated above is instilled into the animal's eye. During an observation period of 2 min after instillation, the number of times each animal rubbed the instilled eye with the ipsilateral forepaw was recorded. For each given group, the percentage of protection was calculated as follows: P=100-((mean value of the number of scratches of the group treated with the compound / mean of the number of scratches of the group treated with the solvent ) x 100 This percentage of protection was averaged for each group of animals (n = number of animals tested with the compound of the invention).

A certain percentage of protection was, in this model, for the most active compounds of the invention, used with a concentration of 500 pM, between 20% and 100% (see example in Table 4):

[0096] The results of these tests show that the most active compounds of the invention block the effects caused by TRPV1 receptor stimulation.

[0097] The compounds of the invention can therefore be used for the production of drugs, especially for the production of drugs for the prevention or treatment of pathologies in which TRPV1-type receptors are involved.

[0098] Thus, according to one of its aspects, the subject of this invention are drugs containing at least one compound of formula (I), or a pharmaceutically acceptable salt, or, on the other hand, a hydrate or solvate of the given compound.

[0099] These drugs are used in therapy, especially in the prevention and/or treatment of pain or inflammation, chronic pain, neuropathic pain (due to trauma, diabetes, metabolism, infections, poisoning, caused by anticancer therapy or iatrogenic), (osteo-) arthritic, rheumatic, fibromyalgia, back pain, cancer-related pain, facial neuralgia, headaches, migraines, toothaches, burns, sunstroke, bites or stings, neuralgia after herpes, muscle pain, pain due to compression of nerves (central and/or peripheral), spinal cord and/or brain trauma, ischemia (spinal cord and/or brain), neurodegeneration, vascular hemorrhagic accidents (spinal cord and/or brain), pain after stroke.

[0100] The compounds of the present invention may also be used in the prevention or treatment of urological disorders, such as bladder overactivity, bladder hyperflexion, bladder instability, incontinence, urinary urgency, urinary urgency, cystitis, renal colic, pelvic hypersensitivity and pelvic pain. The compounds of the present invention may be useful in the prevention and/or treatment of gynecological disorders such as vulvodynia, pain associated with salpingitis and dysmenorrhea. These products may also be useful in the prevention and/or treatment of gastrointestinal disorders, such as gastroesophageal reflex disorder, gastric ulcer, duodenal ulcer, functional dyspepsia, colitis, IBS (Irritable Colon Syndrome), Crohn's disease, pancreatitis, esophagitis, hepatic colic. The compounds of the invention can also be used to obtain drugs for the treatment of diabetes. Also, the products of the present invention can be useful in the prevention and/or treatment of respiratory disorders, such as asthma, cough, chronic obstructive pulmonary disease (COPD), bronchoconstriction and inflammatory disorders. These products can also be used in the prevention and/or treatment of psoriasis, pruritis, skin, eye or mucous membrane irritations, herpes, herpes zoster. The compounds of the invention can also be used in the preparation of drugs for the treatment of depression. .[0101] According to one of its other aspects, this invention concerns pharmaceutical compositions containing, as an active ingredient, a compound according to this invention. These pharmaceutical compositions contain an effective dose of at least one compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as well as at least one pharmaceutically acceptable excipient. These excipients are selected according to the pharmaceutical form and the desired route of administration, from the usual excipients known to the person skilled in the art.

[0102] In the pharmaceutical compositions of this invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I), or its salt, solvate or hydrate, can be administered in the form of unit doses, in a mixture with classical pharmaceutical excipients, to animals and humans for the purpose of prophylaxis or treatment of the mentioned disorders or diseases.

[0103] Suitable unit dosage forms include forms for oral administration, such as

tablets, soft or hard capsules, powders, granules and oral solutions or suspensions; forms for sublingual, buccal, intratracheal, intraocular, intranasal administration, administration by inhalation; forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants. For topical application, the compounds of this invention can be used as creams, gels, pomades or lotions.

[0104] For example, a unit dose of a compound of the present invention, in tablet form, may contain the following ingredients:

[0105] The given unit forms are dosed so as to enable the daily administration of 0.001 to 30 mg of the active ingredient per kg of body weight, depending on the galenic form.

[0106] There may be specific cases where stronger or weaker doses are needed. Those doses

do not go beyond the scope of this invention. According to common practice, the appropriate dose for each patient is determined by the doctor, depending on the method of administration, body weight and reaction of the given patient.

Claims (20)

1. A compound corresponding to formula (I) wherein Xi is a hydrogen atom or a halogen atom or Ci-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, Ci-C6-fluoroalkyl, cyano, C(0)NRiR2, nitro, d-Ce-thioalkyl, -S(0)-Ci-Ce-alkyl, -S(0)2-Ci-C6-alkyl, SO2NRiR2, aryl-d-C6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and d-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-CrC3-alkylene, Ci-C6-fluoroalkyl, Ci-C6-alkyl, Ci-C6-fluoroalkyl, nitro or cyano groups; X2 is a hydrogen atom or a halogen atom or CrC6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyl-d-Cs-alkylene, CrC6-fluoroalkyl, CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkylene-0-, Ci-C6-fluoroalkylene, C(0)NRiR2, cyano. C1-C6-thioalkyl, -S(0)-CrC6-alkyl, -S(0)2-CrC6-alkyl, SO2NRiR2, aryl-CrC6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, C-i-C6-fluoroalkyl, C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, nitro or cyano groups; Xsi and X4 are, independently of each other, a hydrogen or halogen atom or d-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, Ci-C6-fluoroalkyl, CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkylene-0-, d-C6-fluoroalkylene, cyano, C(O)NRiR2, nitro, NR1R2, C1-C6-thioalkyl, -S(0)-d-C6-alkyl, -S(0)2-d-C6-alkyl, SO2NRiR2, NR3COR4, NR3SO2R5, aryl-d-C6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and d-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, d-C6-fluoroalkyl, d-C6-alkyl, C1-C6-fluoroalkyl, nitro or cyano groups; Z 1 , Z 2 , Z 3 and Z 4 are, independently of each other, a nitrogen atom or a C(Re) group, wherein at least one corresponds to a nitrogen atom and at least one corresponds to a C(R 6 ) group; And wherein the nitrogen atom or one of the nitrogen atoms present in the ring, defined as nitrogen in position 1, is optionally substituted with R7 when the carbon atom in position 2 or position 4 relative to the reference nitrogen is substituted with an oxo or thio group; n equal to 0, 1, 2 or 3; Y is aryl or heteroaryl optionally substituted with one or more groups selected from halogen atoms or C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, hydroxyl, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkylene-0-, C1-C6-fluoroalkyl, cyano, 0(0)^^2, nitro, NR1R2, CrC6-thioalkyl, thiol, -S(0>CrC6-alkyl, -S(0)2-CrC6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5, aryl-C1-C6-alkylene or an aryl group, wherein aryl and aryl-C1-C6-alkylene are optional substituted with one or more substituents selected from halogen, i C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, nitro or cyano groups; It is a cyclic amine attached via a nitrogen atom, formula in which A is a C1C7-alkylene group optionally substituted with one or two R3 groups; B is a C1C7-alkylene group optionally substituted with one or two R9 groups; L is a bond, or a sulfur, oxygen or nitrogen atom, wherein the nitrogen atom is optionally substituted with the group R10 or Rn, the carbon atoms of the cyclic amine Z are optionally substituted with one or more R 12 groups which may be identical or different from each other; R 1 R 2 are, independently of each other, a hydrogen atom or d-C 6 -alkyl, C 3 -C 7 -cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, aryl-C1-C6-alkylene, aryl or heteroaryl group; or R1 R2 grade, together with the nitrogen atom bearing them, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, wherein this group is optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-CrC3-alkylene, aryl-CrC6-alkylene, aryl or heteroaryl group; R 3 and R 4 are, independently of each other, a hydrogen atom or a C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene, aryl or heteroaryl group; R5 is C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene, aryl-d-C6-alkylene, aryl or heteroaryl group; R6 is a hydrogen or halogen atom or CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, d-C6-fluoroalkyl, Ci-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-CrC6-alkylene-0-, Ci-C6-fluoroalkyl, Ci-C6-thioalkyl, ^(OJ-d-C6-alkylene). -S(O)2-C1-C6-alkyl, aryl, aryl-d-C6-alkylene, heteroaryl, hydroxyl, thiol, oxo or thio group; R7 is a hydrogen atom or d-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, d-C6-fluoroalkyl, d-C6-Alkoxyl, C3-C7-Cycloalkylene, C3-C7-Cycloalkyl-d-C6-alkylene-O-, C1-C6-fluoroalkyl, aryl, aryl-d-C6-alkylene or heteroaryl group; R 8 , R 8 and R 10 are defined so that: two R 8 groups can together form a bond or a d-C 6 -alkylene group; two Rg groups can together form a bond or a d-C6-alkylene group; R8 and R9 can together form a bond or a d-C6-alkylene group; R8 and R10 may together form a bond or a d-C6-alkylene group; R9 and R10 may together form a bond or a d-C6-alkylene group; Rn is a hydrogen atom or d-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-d-C3-alkylene, CrC6-fluoroalkyl, d-C6-alkyl, d-C7-cycloalkyl, C3-C7-cycloalkyl-d-C6-alkylene-0-, C1-C6-fluoroalkyl, hydroxyl, COOR5, C(0)NR1R2, aryl-C1-C6-alkylene, aryl or heteroaryl group, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, and C1-C6-alkyl, C3-C7-cycloalkyl, C5-d-cycloalkyl-Cr-Oralkylene, C1-C6-fluoroalkyl, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-fluoroalkyl, nitro or cyano groups; R 12 is a fluorine atom, a C 1 -C 6 -alkyl group optionally substituted with a group R 13 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl or CrC6-cycloalk-1,1-diyl group, C3-C7-heterocycloalk-1,1-diyl group optionally substituted on the nitrogen atom with the group Rn, or CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkylene-0-, Ci-C6-fluoroalkyl, C(0)NRiR2, NR1R2, NR3COR4, fJC(0)NRiR2, NR3COOR5, NR3CONRiR2, hydroxyl, thiol, oxo, thio, aryl-Ci-C6-alkylene or aryl group, wherein the aryl is optionally substituted with one or more substituents selected from halogen, and d-Ce-alkyl, Cs-CVcycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, Ci-C6-Fluoroalkyl, Ci-C6-Alkoxyl, C3-C7-cycloalkyl, C1-C6-fluoroalkyl, nitro or cyano groups; R-13 is C1-C6-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene-O-, C(O)NR1R2, NR3s, NR3COR4, OC(O)NR1R2, NR3COOR5 or hydroxyl; wherein it is possible for the nitrogen atom(s) of the compound of formula (I) to be in an oxidized form; wherein it is possible for the sulfur atom(s) of the compound of formula (I) to be in an oxidized form; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate 2. The compound of formula (I) according to Claim 1, characterized in that Xi, X2, X3 and X4 are selected, independently of each other, from hydrogen atoms or halogen atoms or C-i-Ce-alkyl, d-Ce-fluoroalkyl, C-i-C6-thioalkyl or -S(0)2-C1-C6-alkyl groups; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 3. The compound of formula (I) according to Claim, characterized by the fact that Xi is a hydrogen atom or a halogen atom or a Ci-C6-alkyl group; X 2 is a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl, d -C 6 -fluoroalkyl or -S(O) 2 -C 1 -C 6 -alkyl group; X 3 and X 4 are, independently of each other, a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, UR 1 R 2 or C 1 -C 6 -thioalkyl group; R 1 R 2 are, independently of each other, a C 1 -C 6 -alkyl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate 4. A compound of formula (I) according to any one of Claims 1 to 3, characterized in that Zi, Z2, Z3 and Z4 are, independently of each other, a nitrogen atom or a C(Rq) group, wherein at least two of them correspond to a C(R6) group; wherein the nitrogen atom or one of the nitrogen atoms present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or 4 relative to this reference nitrogen is substituted with an oxo or thio group; wherein R 6 and R 7 are defined as in formula (I) according to Claim 1; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 5. The compound of formula (I) according to Claim 4, characterized in that Z1 and Z3 are C(Re) groups and Z2 and Z4 are nitrogen atoms; wherein R 6 corresponds to a hydrogen atom; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 6. The compound of formula (I) according to Claim 4, characterized in that Z-i, Z2, Z3 and Z4 are, independently of each other, a nitrogen atom or a C(Re) group, wherein one corresponds to a nitrogen atom and the other corresponds to a C(R6) group; wherein the nitrogen atom present in the ring, defined as nitrogen in position 1, is optionally substituted with R7, when the carbon atom in position 2 or 4 relative to this reference nitrogen is substituted with an oxo or thio group; wherein R 6 and R 7 are defined as in formula (I) according to Claim 1; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 7. The compound of formula (I) according to Claim 6, characterized in that Za is a nitrogen atom and Z-i, Z2i Z3 are, independently of each other, a C(R6> group; R 6 is a hydrogen atom or a C 1 -C 6 -alkyl, C 1 -C 6 -fluoroalkyl or C 1 -C 6 -alkyl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 8. A compound of formula (I) according to any one of Claims 1 to 7, characterized in that n is equal to 1; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 9. A compound of formula (I) according to any one of Claims 1 to 8, characterized in that Y is aryl or heteroaryl optionally substituted with one or more groups selected from halogen atoms or C1-C6-alkyl or NR1R2 groups; R1 R2 is, together with the nitrogen atom bearing it, an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, wherein this group is optionally substituted with a CrC6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C3-alkylene, aryl-Ci-C6-alkylene, aryl or heteroaryl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 10. The compound of formula (I) according to any one of Claims 1 to 9, characterized in that Z is a cyclic amine attached via a nitrogen atom, of the formula: in which A is a C 1 -C 4 -alkylene group optionally substituted with one or two Re groups; B is a C1-C4-alkylene group optionally substituted with one or two R9 groups; L is a bond or an oxygen atom; whereby it is possible for the nitrogen atom of the cyclic amine Z to be in the form of N-oxide; wherein the atoms of the cyclic amine Z are optionally substituted with the group R12; R8 and R9 are defined so that: two Rgroups can build a bond together; or two Rg groups can form a bond together; or R8 and Rg can build a connection together; R 12 is NR 1 R 2 , NR 3 COOR 5 or a hydroxyl group; R 1 and R 2 are, independently of each other, a hydrogen atom; R 3 is a hydrogen atom; R 5 is a C 1 -C 6 -alkyl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 11. A compound of formula (I) according to Claim 10, characterized in that Z is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyclo[3.1.0]hexane and azabicyclo[3.2.0]heptane; whereby it is possible for the nitrogen atom of the cyclic amine Z to be in the form of N-oxide; wherein the atoms of the cyclic amine Z are optionally substituted with the group Ri2; R 12 is NR 1 R 2 , NR 3 COOR 5 or a hydroxyl group; R 1 R 2 are, independently of each other, a hydrogen atom; R3 is a hydrogen atom;; R 5 is a C 1 -C 1 -alkyl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 12. The compound of formula (I) according to Claim 11, characterized in that Z is a cyclic amine selected from azetidine, pyrrolidine, piperidine, morpholine, azabicyl[3.1.0]hexane and azabicyl[3.2.0]heptane; wherein the carbon atoms of azetidine are optionally substituted with a hydroxyl group; whereby the carbon atoms of pyrrolidine are optionally substituted with NR 3 , NR 3 COOR 5 or a hydroxyl group; whereby it is possible for the pyrrolidine nitrogen atom to be in the form of N-oxide; R 1 R 2 are, independently of each other, a hydrogen atom; R 3 is a hydrogen atom; R 5 is a C 1 -C 6 -alkyl group; in the form of a base or addition salt of an acid, and also in the form of a hydrate or solvate. 13. Process for obtaining compounds of formula (I) according to any one of Claims 1 to 12, characterized in that the compound of formula (IV) wherein X, X2, X3, X4, Y and n are as defined in formula (I) according to Claim 1 and B is a chlorine atom, reacted with an amine of formula (V) wherein Z 1 , Z 2 , Z 3 , Z 4 and Z are as defined in formula (I) according to Claim 1, in a solvent. 14. Process for obtaining compounds of formula (I) according to any one of Claims 1 to 12, characterized in that the compound of formula (IV) wherein Xi, X2, X3, X4, Y and n are as defined in formula (I) according to Claim 1 and B is a hydroxyl group, reacted with an amine of formula (V) wherein Z-i, Z2, Z3, Z4 and Z are as defined in formula (I) according to Claim 1, in the presence of a coupling agent and a base in the solvent. 15..A process for obtaining a compound of formula (I) according to any one of Claims 1 to 12, characterized in that the compound of formula (VI) wherein Xi, X2, X3, X4, Zi, Z2, Z3, Z4, Y and n are as defined in formula (I) according to Claim 1 and W is a halogen atom, reacted in the presence of an amine of formula ZH wherein Z is a cyclic amine as defined in formula (I) according to Claim 1. 16. The amine of formula (V) selected from the following amines: in the form of a base or acid addition salt. 17. Medicine, characterized in that it contains a compound of formula (I) according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt, or hydrate or solvate of a compound of formula (I). 18. A pharmaceutical composition, characterized in that it contains a compound of formula (I) according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt, or hydrate or solvate of this compound, and also at least one pharmaceutically acceptable excipient. 19. Use of a compound of formula (I) according to any one of Claims 1 to 12, for obtaining a drug for the prevention or treatment of pathologies in which TRPV1-type receptors are involved. 20. Use of a compound of formula (I) according to any one of Claims 1 to 12, for obtaining a medicament for the prevention or treatment of pain, inflammation, urological disorders, gynecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritis, dermal, ocular or mucosal irritations, herpes or herpes zoster, or for the treatment of depression or diabetes.